biostudies-literatureUnknown9(34)Sun RRegulatory T (T_reg) cells and cancer-associated fibroblasts (CAFs) jointly promote tumor immune tolerance and tumorigenesis. The molecular apparatus that drives T_reg cell and CAF coordination in the tumor microenvironment (TME) remains elusive. Interleukin 33 (IL-33) has been shown to enhance fibrosis and IL1RL1⁺ T_reg cell accumulation during tumorigenesis and tissue repair. We demonstrated that IL1RL1 signaling in T_reg cells greatly dampened the antitumor activity of both IL-33 and PD-1 blockade. Whole tumor single-cell RNA sequencing (scRNA-seq) analysis and blockade experiments revealed that the amphiregulin (AREG)-epidermal growth factor receptor (EGFR) axis mediated cross-talk between IL1RL1⁺ T_reg cells and CScience advanceseadd7399https://www.ebi.ac.uk/biostudies/studies/S-EPMC10446484biostudies-literatureAmphiregulin couples IL1RL1⁺ regulatory T cells and cancer-associated fibroblasts to impede antitumor immunity.PMC10446484Li HChen KLu XSun RChen LNi AGao DSZhao HLu BfalseAmphiregulin couples IL1RL1⁺ regulatory T cells and cancer-associated fibroblasts to impede antitumor immunity.Regulatory T (T_reg) cells and cancer-associated fibroblasts (CAFs) jointly promote tumor immune tolerance and tumorigenesis. The molecular apparatus that drives T_reg cell and CAF coordination in the tumor microenvironment (TME) remains elusive. Interleukin 33 (IL-33) has been shown to enhance fibrosis and IL1RL1⁺ T_reg cell accumulation during tumorigenesis and tissue repair. We demonstrated that IL1RL1 signaling in T_reg cells greatly dampened the antitumor activity of both IL-33 and PD-1 blockade. Whole tumor single-cell RNA sequencing (scRNA-seq) analysis and blockade experiments revealed that the amphiregulin (AREG)-epidermal growth factor receptor (EGFR) axis mediated cross-talk between IL1RL1⁺ T_reg cells and C2023-01-01T00:00:00Z2023 Aug2025-04-26T23:29:40.35Z2025-04-06T17:35:47.147ZS-EPMC104464843761111110.1126/sciadv.add7399